This proposal addresses Theme 4 (Focusing on global health) of NIH RFA-OD-10-005 by aiming to generate staphylococcal vaccines. The project also addresses Theme 1 (Applying Genomics and Other High Throughput Technologies) through the systematic analysis of human B cell responses as well as Theme 2 (Translating Basic Science Discoveries into New and Better Treatments) through the invention of a novel treatment - therapeutic vaccination - for human MRSA infections. Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the world. Antibiotic resistant strains (MRSA) are isolated in more than half of all community and hospital infections, and humans that survive MRSA infections do not develop protective immunity. We report that MRSA evasion from host protective immune responses is triggered by two surface molecules, adenosine synthase A (AdsA) and protein A (SpA). AdsA produces the immune suppressive molecule adenosine, whereas SpA triggers the apoptotic collapse of B cell immune responses. Studies on host immune responses to challenge with attenuated S. aureus strains and on the immunity elicited from purified staphylococcal subunit antigens lead us to propose that protective immunity against MRSA is achieved via neutralizing antibodies, which block the pathogen's coagulation and agglutination strategies during infection. Enabled by the availability of an exciting new technology - high-throughput isolation of monoclonal antibodies from human plasmoblasts - we propose here the systematic analyses of B cell responses for neutralizing antibodies against staphylococcal AdsA, SpA, coagulases and agglutinins. These antibodies will be used to define the hitherto elusive attribute of protective immunity against MRSA infections using in vitro assays and animal models for staphylococcal diseases. Once endowed with such information, we will generate immune therapeutics for the treatment of MRSA infections and vaccines to globally prevent staphylococcal infections. This ARRA proposal represents a one-time investment into a unique knowledge gap and a technological opportunity with a probable quantum yield of returns in translational products. Beyond its initial phase of discovery, this research program is designed to attract private resources leading to the development of vaccines that can protect humans from disease and thereby improve Global Health. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus, in particular antibiotic resistant isolates (MRSA), are a leading cause of infectious disease morbidity and mortality in the world. However, vaccines or immune therapeutics against MRSA are not available. During staphylococcal infection, protein A, coagulase and von-Willebrand-Factor binding-protein impart toxic functions on blood clotting or immune suppression that can be overcome through the generation of specific immune responses directed against these factors. These technologies will be developed with the goal of generating a vaccine and immune therapeutics, thereby providing protection against S. aureus infections and improving global health.